DEFINITION

Myopathy means muscular disease, and generally refers to a disorder in which muscle weakness develops due to some malfunction of the actual muscle fibers.

EPIDEMIOLOGY

One third of heavy long-term alcohol consumption (of any beverage type), aka alcoholics, in both sexes and all races, develop skeletal myopathy. The acute form is four times more common in males than females.

SYMPTOMS

Alcoholic myopathy can have serious symptoms and side effects.
There are usually no symptoms until the disease is in an advanced stage. At that point, the symptoms occur due to heart failure and may include:

Ankle, feet, and leg swelling

Awakening during the night with shortness of breath (paroxysmal nocturnal dyspnea)

Breathing difficulty while lying down (orthopnea)

Cough containing mucus, or pink, frothy material

Decreased alertness or concentration

Decreased urine output (oliguria)

Fatigue, weakness, faintness

Irregular or rapid pulse

Loss of appetite

Need to urinate at night (nocturia)

Overall swelling

Sensation of feeling the heart beat (palpitations)

Shortness of breath, especially with activity (dyspnea)

Muscle Symptoms

In the acute form of alcoholic myopathy, muscle pain, tenderness, swelling and weakness may be the first symptoms noted after waking from an alcoholic stupor after binge drinking. Pain in the calf similar to the pain of deep vein thrombosis may occur. In severe cases of acute alcoholic myopathy, muscles of the throat, diaphragm and upper chest may also begin to break down. Muscle breakdown in acute disease may be exacerbated by crush or compression injuries that occur when muscles groups are compressed for long periods of time after an alcoholic passes out. Painless proximal muscle atrophy, with a striking decrease in muscle bulk and weakness develop in chronic myopathy, with the hips, shoulders, thighs and upper arms most notably affected.

Renal Symptoms

The breakdown of muscle tissue releases myoglobin, which is excreted in the urine. Urine may turn red from myoglobin. Myoglobin release, along with other enzymes such as creatine kinase, can also cause acute renal, or kidney, failure, Singh warns. Acute renal failure may require temporary dialysis until the kidneys recover.

Cardiac Symptoms

Alcoholic myopathy can weaken the heart muscles, leading to cardiomyopathy. Severe disease can lead to increased serum potassium levels from muscle breakdown, which can cause heart arrhythmias and irregular beats. Abnormal heart rhythms can cause death in some cases.

DIAGNOSIS

In case of alcoholic cardiomyopathy the diagnosis includes the detection of abnormal heart sounds, murmurs, ECG abnormalities, and enlarged heart on chest x-ray may lead to the diagnosis. Echocardiogram abnormalities and cardiac catheterization or angiogram to rule out coronary artery blockages, along with a history of alcohol abuse can confirm the diagnosis.

PATHOGENESIS

Acute Alcoholic Myopathy

Acute alcoholic myopathy develops suddenly, during an episode of binge drinking or immediately following during withdrawal. Acute alcoholic myopathy is also called “alcoholic rhabdomyolysis”. It can come on rapidly over the course of a few hours and can advance over a few days before receding over the week, given the individual abstains from alcohol. Acute myopathy can present mild to severe symptoms as a result of myonecrosis, the breakdown of muscle tissue.

Symptoms of acute alcoholic myopathy may include muscle pain and swelling in addition to the classic weakness. Often the acute symptoms are reported upon awakening from an alcoholic stupor; they may also accompany withdrawal symptoms and delirium tremens. Tests have revealed that acute alcoholic myopathy affects type I muscle fibers, which can heal rapidly; however type II muscle fibers are involved in chronic alcoholic myopathy.

Typically, full recovery from acute alcoholic myopathy occurs in a matter of days or weeks; however, in extreme cases when kidney failure or hyperkalemia (abnormal potassium level in the blood) occur, the alcoholic may actually die during the episode of acute myopathy. Otherwise, research has shown it takes about 7 to 10 days for the serum creatine kinase levels (reflecting the health of the muscle) to return to normal range.

Chronic Alcoholic Myopathy

In contrast to the acute form, chronic alcoholic myopathy develops much more gradually and lasts far longer. While the acute version may include muscle pain, chronic alcoholic myopathy is usually painless. The absence of pain and gradual onset may explain why it is frequently overlooked and not diagnosed until the symptoms have been present for several years. The recovery time for chronic myopathy is slower and can take many months.

Chronic alcoholic myopathy is associated with long term alcohol abuse (years of daily alcoholic drinking). It evolves slowly, over weeks or months as opposed to its acute counterpart which can develop in a matter of hours or days. The main symptom of chronic alcoholic myopathy is muscle weakness and atrophy. It affects proximal muscles, and type 2 muscle fibers. Interestingly, long term corticosteroid use can lead to similar type 2 atrophy as well, a.k.a. “steroid myopathy”.

Other disorders which may co-occur with chronic alcoholic myopathy include peripheral neuropathy. While with myopathy the primary dysfunction exists within the muscle itself, with neuropathy the dysfunction pertains to the nervous system (nerves or brain).

Effect of EtOH on cell proliferation: the experiments were performed during the first 4 days of culture. Thymidine incorporation showed a tendency to increase for the first 3 days. Exposure of cells to EtOH for only 1 day produced a significant inhibition of proliferation at all EtOH concentrations. This inhibition increased with increasing EtOH concentration (from 10 mM to 100mM). After 2 days of EtOH exposure, the inhibitory effect of EtOH was only significant for the highest concentration (100 mM).
Effect of EtOH on cell differentiation: to determine the effects of EtOH on cell differentiation researchers measured the percentage of the three CK isozymes, which are known to change depending on the state of differentiation. EtOH (in different concentrations) was added on day 5 of the culture, as differentiation began, and the percentage of each isoform was then found to be 31.8% (MM), 14.8% (MB), and 53.5% (BB). As differentiation progressed, the percentage of MM increased to 61% and BB decreased significantly to 12.7% on day 12. Because there was no EtOH dose-dependent effect (results not shown), researchers analysed the pooled results obtained with different concentrations. MM and MB activities both decreased, whereas that of BB increased significantly after EtOH treatment. Although total CK activity did not change in the presence of EtOH, the percentage of isoforms did. The result suggests that EtOH delays cell differentiation. EtOH exerted no significant effects on DNA or protein concentrations. The effect of EtOH on these two parameters was also studied when cells were completely differentiated. As occurred during differentiation, EtOH did not affect the protein or DNA levels, and there were therefore no significant changes in protein/DNA ratio when the cells grew in the presence of EtOH.

THERAPY FOR ALCOHOLIC MYOPATHY AND ALCOHOLIC CARDIOMYOPATHY

Treatment for alcoholic myopathy involves lifestyle changes, including complete abstinence from alcohol use, a low sodium diet, and fluid restriction, as well as medications. Medications for alcoholic cardiomyopathy may include ACE inhibitors, beta blockers, and diuretics which are commonly used with other forms of cardiomyopathy to reduce the strain on the heart. Persons with congestive heart failure may be considered for surgical insertion of an ICD or a pacemaker which can improve heart function. In cases where the heart failure is irreversible and worsening, heart transplant may be considered.

ALCOHOL AND LETHAL ARRHYTHMIAS

Alcohol is not only correlated to dilated cardiomyopathy. There are several studies which show that heavy alcohol consumption plays an important role in worsening the cardiac situation of those patients (often young people) who suffer from genetic arrhythmic syndromes.

For example, overindungence in alcohol increases the risk of ventricular fibrillation (VF) in patients with Brugada Syndrome (BrS) (for further information about the pathology see Sodium channels-Brugada Syndrome, 2011). Nowadays this rare lethal syndrome is considered due to mutations in SCN5A and in other genes (Genetic bases for the Brugada syndrome, 2009). Nevertheless, a lot of different substances have been connected with the onset of VF in these patients: alcohol appears among these drugs, although there is divergence of opinions about it.

The ethanol concentration that causes this bad functioning of L-type calcium channel (espression of the CACNA1C gene, the same whose mutation has been correlated to BrS, see the table above) in the whole cardiac mass is clinically relevant (24mM, approximately corrisponding to 1,1g/l). It means that alcoholic drinks can contribute to the sudden onset of cardiac arrhythmia.

Alcohol reduces mitochondrial respiration in heart cells (Alcoholic depression of oxidative phosphorylation, 2007). The concentrations which determine this kind of effect on respiration are very high, fully out of physiological levels. In spite of this, there is no reason for doubting whether these effects could be generated by lower ethanol quantities, although in a weaker way.
In this condition, ATP levels in the cells drop: the major consequences are that myosin is blocked and SERCA (Ca++ ATPase placed on Sarcoplasmic Reticulum), Na+/K+ ATPase and Sodium-Calcium Exchanger (in the plasmatic membrane) don't function correctly. This leads to a raise of Ca++ in cardiomyocytes, with an increased risk of fibrillation.

An other consequence is that adenylate cyclase does not work properly. The production of cAMP goes down: the main result is a reduced response to norepinephrine (NE) and catecholamines in general. This event leads to a negative inotropic effect on heart, which has been identified as possible cause of life-threatening arrhythmogenesis (Reduction of NE and cAMP in heart cells can provoke lethal arrhythmias, 2011).

In this picture we can see that PKA phosphorylates L-type calcium channels, favouring their opening. When cAMP is low, PKA is inhibited and calcium channels are less open. It is one of the cellular pathways by which negative inotropic effect happens.